The present invention pertains at least in part to cancer treatment, certain chemical compounds, and methods of treating tumors and cancers with the compounds.
RON (recepteur d'origine nantais) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. It is activated by binding to its natural ligand MSP and signals via the PI3K and MAPK pathways. RON can be deregulated in cancer by mechanisms such as over-expression of the receptor and/or the presence of constitutively active splice variants. Inhibition of RON has been shown to lead to a decrease in proliferation, induction of apoptosis and affects cell metastasis. RON overexpression is observed in a variety of human cancers and exhibits increased expression with progression of the disease.
MET (also known as c-Met) is a receptor tyrosine kinase that is a heterodimeric protein comprising of a 50 kDa α-subunit and a 145 kDa β-subunit (Maggiora et al., J. Cell Physiol., 173:183-186, 1997). It is activated by binding to its natural ligand HGF (hepatocyte growth factor, also known as scatter factor) and signals via the PI3K and MAPK pathways. MET can be deregulated in cancer by mechanisms such as autocrine/paracrine HGF activation, over-expression of the receptor, and/or the presence of activating mutations. Significant expression of MET has been observed in a variety of human tumors, such as colon, lung, prostate (including bone metastases), gastric, renal, HCC, ovarian, breast, ESCC, and melanoma (Maulik et al., Cytokine & Growth Factor Reviews 13:41-59, 2002). MET is also implicated in atherosclerosis and lung fibrosis. Inhibition of MET can cause a decrease in cell motility, proliferation and metastasis, as reviewed in, e.g., Chemical & Engineering News 2007, 85 (34), 15-23.
Elevated expression of cMET has been detected in numerous cancers including lung, breast, colorectal, prostate, pancreatic, head and neck, gastric, hepatocellular, ovarian, renal, glioma, melanoma, and some sarcomas (see reviews Christensen, J., 2005; Comoglio, P., 2008). cMET gene amplification and resulting overexpression has been reported in gastric and colorectal cancer (Smolen, G., 2005; Zeng Z., 2008). Taken together, the cMET proto-oncogene has a role in human cancer and its over-expression correlates with poor prognosis. Abrogation of cMET function with small molecule inhibitors, anti-cMET antibodies or anti-HGF antibodies in preclinical xenograft model systems has shown impact when cMET signaling serves as the main driver for proliferation and cell survival (Comoglio, P., 2008).
As human cancers progress to a more invasive, metastatic state, multiple signaling programs regulating cell survival and migration programs are observed depending on cell and tissue contexts (Gupta and Massague, 2006). Recent data highlight the transdifferentiation of epithelial cancer cells to a more mesenchymal-like state, a process resembling epithelial-mesenchymal transition (EMT); (Oft et al., 1996; Pert et al., 1998), to facilitate cell invasion and metastasis (Brabletz et al., 2005; Christofori, 2006). Through EMT-like transitions mesenchymal-like tumor cells are thought to gain migratory capacity at the expense of proliferative potential. A mesenchymal-epithelial transition (MET) has been postulated to regenerate a more proliferative state and allow macrometastases resembling the primary tumor to form at distant sites (Thiery, 2002). MET and RON kinases have been shown to play a role in the EMT process (Camp et al., 2007; Grotegut et al., 2006; Wang et al., 2004). It has been documented in vitro that RON and MET can form heterodimers and signal via such RON-MET dimers.
cMET and RON are known to interact and influence the activation of one another. Furthermore, co-expression of the two receptors, when compared to each receptor alone, is associated with the poorest clinical prognosis in bladder, CRC, and breast cancer patients. Since co-expression of RON and MET in cancer has been observed, such “cross-talk” may contribute to tumor growth.
The following published documents are also noted: WO08/051,808; WO08/051,805; WO08/008,539; WO08/039,457; WO07/138,472; WO07/132,308; WO07/075,567; WO07/067,537; WO07/064,797; WO05/010005; WO05/004607; U.S. Pat. No. 7,230,098; US2007/287711; US2005/182060; US2006/128724; US2007/060633; US2007/049615; US2007/043068; US2007/032519; US2007/012535; US2006/046991; Wang et al., J. Appl. Poly. Sci., 109(5), 3369-3375 (2008).
There is a need for effective therapies for use in proliferative disease, including treatments for primary cancers, prevention of metastatic disease, and targeted therapies, including tyrosine kinase inhibitors, such as MET and/or RON inhibitors, dual inhibitors, including selective inhibitors, and for potent, orally bioavailable, and efficacious inhibitors, and inhibitors that maintain sensitivity of E cells to epithelial cell directed therapies.